- ICH GCP
- Registre américain des essais cliniques
- Essai clinique NCT01334073
Study of the Combination of Axitinib Plus Everolimus in Patients With Malignant Advanced Solid Tumors (EVAX)
Phase I Study of the Combination of Axitinib (AX) Plus Everolimus (EV) in Patients With Malignant Advanced Solid Tumors
Aperçu de l'étude
Statut
Les conditions
Intervention / Traitement
Description détaillée
Phase I study of the combination of axitinib (AX) plus everolimus (EV) in patients with malignant advanced solid tumors.
- To determine the recommended dose for phase II study of the combination of AX + EV
- To determine the safety profile and predictive factors for toxicity, pharmacokinetics (PK), and efficacy in adult solid tumors.
- To assess functional vascular imaging (FVI) as surrogate marker of activity, biomarkers predictive of activity and preliminary efficacy data in metastatic RCC, untreated with antiangiogenics.
Phase I, multicentre, open-label, non-randomized, sequential algorithm based dose-finding (3+3), clinical study in successive cohorts of patients.
Patients will take both drugs orally, every day, without planned rest period (AX bid and EV once a day). By convention one cycle is 28 days. At the first cycle patients will take one week of AX single agent before starting EV. Patients will be treated at increasing dose levels (DLs) in successive cohorts of 3-6 patients according to the number of patients with dose limiting toxicities (DLT) until the maximum tolerated dose (MTD; i.e. the DL at which <= 1/6 patient experiences a DLT during the first cycle). All decision concerning qualification for DLT, dose escalation, study termination, inclusion of additional patients, will be taken by a Trial Monitoring Committee..
The MTD will not be higher than the recommended dose of each single agent. Six additional patients will be entered at the MTD to confirm the feasibility of the dose and preliminarily assess the efficacy of the combination in patients with RCC untreated with antiangiogenics.
Three levels of dose will be explored.
Type d'étude
Inscription (Réel)
Phase
- La phase 1
Contacts et emplacements
Lieux d'étude
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Bordeaux, France, 33000
- Professeur Alain RAVAUD
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Toulouse, France, 31000
- Professeur Jean-Pierre DELORD
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Critères de participation
Critère d'éligibilité
Âges éligibles pour étudier
Accepte les volontaires sains
Sexes éligibles pour l'étude
La description
Inclusion criteria
- Histologically proven advanced adult solid tumors, with the exception of Hodgkin and non Hodgkin lymphoma. Patients with hepatocellular carcinomas (HCC) may be enrolled without histological documentation if they meet the consensus non-invasive diagnostic criteria.
- Failure or contra-indication of all standard therapies, except for the patients with advanced renal cell carcinoma, enrolled at the recommended dose who will be naïve of previous lines of therapy while metastatic.
- Age > 18 years
- ECOG Performance status (PS) 0-1
- Life expectancy > 3 months
- Measurable/evaluable disease according to RECIST CRITERIA version 1.0
- Acceptable biological values: Hemoglobin > 10g /dL; neutrophils > 1.5 x 109/L; platelets > 100 x 109/L, AST and ALT < 2.5 x the upper normal limits (UNL), or < 5 x UNL in case of liver metastases, GGT < 3 x the upper normal limits (UNL), PAL < 2.5 x the upper normal limits (UNL), or < 5 x UNL in case of liver metastases, serum bilirubin < 1.5 x ULN, creatinine clearance (Cockroft & Gault formula) > 60 mL/min.
- 24 hours proteinuria ≤ 1 g/24 h
- Albumin > 30 g/l
- Amylase and lipase ≤ 1.5 UNL
- Electrolytes (calcium, sodium, potassium, chlore, magnesium, phosphate) in the normal range. Supplementation could be possible before study entry.
- Total cholesterol ≤ 2.5 UNL
- Triglycerides ≤ 2.5 UNL
- BP < 140/90
- Washout period from last anticancer therapy, including radiation and surgery > 3 weeks and recovery of toxicities to NCI-CTC grade < 1.
- Written informed Consent.
- Use of effective contraceptive method (Intrauterine device, oral combined contraceptive) for women of child-bearing age or whose partner is included in the trial.
- Patient with french social security.
- Additional inclusion criteria before the association axitinib plus everolimus period
- No toxicity with NCI-CTC grade > 2 at the end of axitinib alone period just before starting axitinib and everolimus (cycle 1)
- BP < 140/ 90
Exclusion criteria
- Brain metastasis
- Severe underlying cardiovascular disease, even medically controlled, such as angina pectoris, myocardial infarction, cardiac insufficiency, cardiac failure, cerebral strokes, lower limb ischemic disease, thromboembolic disease, and any patient, who, in the investigator's opinion is at high risk for arterial or venous thromboembolism.
- Hepatitis B or C carrier or at a chronic state
- Uncontrolled hypertension, or diabetes mellitus despite medical treatment.
- Inability to swallow pills
- Unresolved pneumopathy, no need for antibiotherapy
- Any medical or social condition, which; in the investigator's opinion, would jeopardize patient's safety, patient's compliance to the protocol, or the interpretation of study results. These conditions include (but are not limited to): severe infection, cardiac failure, chronic gastrointestinal disease compromising oral drug absorption, psychiatric illnesses, foreseeable poor treatment compliance with oral medications, patients living far away from the investigational centers, etc…
- Hypersensitivity to Axitinib or Everolimus
- Participation to another clinical trial, or use of an unapproved medication within 4 weeks prior to study treatment initiation.
- Pregnant or lactating women.
Plan d'étude
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: N / A
- Modèle interventionnel: Affectation à un seul groupe
- Masquage: Aucun (étiquette ouverte)
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
---|---|
Expérimental: Axitinib plus everolimus
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Patients will take both drugs orally, every day, without planned rest period (AX bid and EV once a day).
By convention one cycle is 28 days.
At the first cycle patients will take one week of AX single agent before starting EV.
Patients will be treated at increasing dose levels (DLs) in successive cohorts of 3-6 patients according to the number of patients with dose limiting toxicities (DLT) until the maximum tolerated dose
|
Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
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Proportion of patients with DLT (dose limiting toxicity) during the first cycle (first 28 days of the combination of both study compounds), per dose level explored
Délai: during cycle 1
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A DLT will be one of the following adverse events, with a possible relationship to the study medications
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during cycle 1
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Mesures de résultats secondaires
Mesure des résultats |
Description de la mesure |
Délai |
---|---|---|
Adverse event (AE) will be graded according to NCI-CTC criteria V3
Délai: After each cycle of treatement
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Number of AE per patient, per grade, per cycle and per dose level, proportion
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After each cycle of treatement
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Best response rate will be assessed according to RECIST criteria, during the follow-up
Délai: Every other cycle of treatment
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Frequency (total, per dose level), proportion
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Every other cycle of treatment
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Rate of non-tumor progression at 16 weeks
Délai: at 16 weeks
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Frequency (total, per dose level), proportion
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at 16 weeks
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Progression-free Survival (PFS) defined as the time between study treatment initiation and either tumor progression or death, regardless of the cause, whichever occurs first and PFS at 1 year
Délai: 1 year
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Frequency (total, per dose level), probability
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1 year
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Comparison of PK parameters
Délai: day 1 (axitinib alone) and day 15 (everolimus combined with axitinib)
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Plasma PK using peak concentration (Cmax), area under the concentration versus time curve (AUC), volume of distribution at steady state (Vdss), plasma clearance (CL) and plasma half-life (t1/2).
PK parameters will be compared to severe (grade 3-4) AEs, tumor responses and non-tumor progression at 16 weeks.
PK parameters of axitinib combined to everolimus (day 15) will be compared to PK parameters of axitinib alone in the same patient (day 1).
PK of everolimus combined to axitinib (day 15) will be compared to historical data of everolimus alone
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day 1 (axitinib alone) and day 15 (everolimus combined with axitinib)
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Collaborateurs et enquêteurs
Parrainer
Les enquêteurs
- Chercheur principal: Alain RAVAUD, University Hospital, Bordeaux
Publications et liens utiles
Publications générales
- Su Y, Amiri KI, Horton LW, Yu Y, Ayers GD, Koehler E, Kelley MC, Puzanov I, Richmond A, Sosman JA. A phase I trial of bortezomib with temozolomide in patients with advanced melanoma: toxicities, antitumor effects, and modulation of therapeutic targets. Clin Cancer Res. 2010 Jan 1;16(1):348-57. doi: 10.1158/1078-0432.CCR-09-2087. Epub 2009 Dec 22.
- O'Reilly T, Lane HA, Wood JM, Schnell C, Littlewood-Evans A, Brueggen J, McSheehy PM. Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model. Cancer Chemother Pharmacol. 2011 Jan;67(1):193-200. doi: 10.1007/s00280-010-1307-z. Epub 2010 May 30.
- Choueiri TK. Axitinib, a novel anti-angiogenic drug with promising activity in various solid tumors. Curr Opin Investig Drugs. 2008 Jun;9(6):658-71.
Dates d'enregistrement des études
Dates principales de l'étude
Début de l'étude
Achèvement primaire (Réel)
Achèvement de l'étude (Réel)
Dates d'inscription aux études
Première soumission
Première soumission répondant aux critères de contrôle qualité
Première publication (Estimation)
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Estimation)
Dernière mise à jour soumise répondant aux critères de contrôle qualité
Dernière vérification
Plus d'information
Termes liés à cette étude
Mots clés
Termes MeSH pertinents supplémentaires
- Tumeurs par type histologique
- Tumeurs
- Tumeurs urologiques
- Tumeurs urogénitales
- Tumeurs par site
- Maladies rénales
- Maladies urologiques
- Adénocarcinome
- Carcinome
- Tumeurs, glandulaires et épithéliales
- Tumeurs rénales
- Carcinome à cellules rénales
- Effets physiologiques des médicaments
- Mécanismes moléculaires de l'action pharmacologique
- Inhibiteurs d'enzymes
- Agents antinéoplasiques
- Agents immunosuppresseurs
- Facteurs immunologiques
- Inhibiteurs de protéine kinase
- Axitinib
- Évérolimus
Autres numéros d'identification d'étude
- CHUBX 2010/09
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